Method for the control of fertility

ABSTRACT

B. A COMPLEX OF A QUATERNARY AMMONIUM COMPOUND OF Formula I and a tetracycline; C. MIXTURES OF QUATERNARY AMMONIUM COMPOUNDS OF Formula I; and, D. COMPLEXES OF (C) AND A TETRACYCLINE.   A method and composition for the control of fertility comprising an antifertility effective compound selected from the group consisting of A. A QUATERNARY AMMONIUM COMPOUND OF THE FORMULA

United States. Patent Dalgard et al.

[111 3,869,550 [451' Mar. 4, 1975 METHOD FOR THE CONTROL OF FERTILITY[75] Inventors: Dan W. Dalgard, Springfield, Va;

Donald E. Coval, Sheridan, Ind.

[73] Assignee: Environmental Science Corporation,

Vienna, Va.

[22] Filed: Apr. 11,1973

[21] Appl. No.: 349,285

Related U.S. Application Data [63] Continuation-impart of Ser. No.249,230, May 1,

1972, abandoned.

[52] U.S. Cl. 424/227, 424/329 1 Int. Cl A61k 27/00 Field of Search424/329, 227

[56] References Cited UNITED STATES PATENTS 2,907,693 10/1959 Price eta1 424/329 3,085,933 4/1963 Schooley et al. 424/329 3,164,607 1/1965Lednicer 260/3265 3.272,70l 9/1966 Kaitz et a1 424/329 3,277,106 10/1966Bencze et :11. 260/295 3,497,559 2/1970 Petracek 424/329 3,686,4168/1972 Myer ct ill. 424/329 OTHER PUBLICATIONS Chem. Abst., 8thCollective lndex, Vol. 66-75,

(1967-1971). pages 20915 & 20 925. Khera et 11., Chem. Abst., Vol. 73,(1970), page 54378e.

Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Laurence, Stokes &Neilun 57 ABSTRACT A method and composition for the control of fertilitycomprising an antifertility effective compound selected from the groupconsisting of a. a quaternary ammonium compound of the b. a complex of aquaternary ammonium compound of Formula 1 and a tetracycline;

c. mixtures of quaternary ammonium compounds of Formula 1; and,

d. complexes of (c) and a tetracycline.

13 Claims, No Drawings METHOD FOR THE CONTROL OF FERTILITY Thisapplication is a continuation-in-part of copending application Ser. No.249,230 filed May 1, 1972 by the present applicants, now abandoned.

This invention is directed to a method of controlling fertility,especially in animals, especially mammals. This invention is furtherdirected to a composition for the control of fertility in mammals.

Recently much concern has been expressed by civic and humanitarianleaders regarding the population explosion in both humans and animals.

Of concern is the eradication of rodent and wild animals population by ameans which does not employ poisons which are potentially dangerous tohumans especially children and/or domestic animals.

Many of the means presently employed in the control of fertility,especially in animals, comprise nonreversible processes or produce sideeffects because of the prolonged utilization of the effective compoundslimiting their usefulness.

Procedures utilizing contraceptive compounds normally require theadministration of the compounds during regular cycles in order toprevent conception. These present methods do not normally preventconception if the contraceptive compound is administered after mating.

It is thus an object of this invention to overcome the disadvantagesenumerated above.

It is another object of this invention to provide a composition havingantifertility properties.

It is still another object of this invention to provide a compositionhaving antifertility properties in post mating utilization.

It is a further object of this invention to provide a method for thecontrol of fertility, i.e., reproduction.

It is still further an object of this invention to provide a method forthe control of fertility in animals, espe cially mammals.

It is a yet still further object of this invention to provide a catand/or dog food which will control fertility in the animal.

Further objects, advantages and aspects of this invention will beapparent from the following description.

In the control of fertility, it is not always possible to ensure thatthe subject will receive the effective composition prior to mating. Thisis especially pertinent in the control of the wild animal population bythe interruption of their reproductive capabilities.

It has now been found that quaternary ammonium compounds have thecapability of controlling fertility if administered at the time ofmating or within an effective period after mating. It has also ben foundthat the antifertility compounds of the invention may, if desired beutilized in the form of a quaternary ammonium tetracycline complex.

The quaternary ammonium compound of this invention is characterized bythe following formula:

wherein R is selected from the group'consisting of alkyl having amaximum of 22 carbon atoms, phenyl, benzyl, R O and HOR O wherein R isalkyl having a maximum of 5 carbon atoms and R is alkylene having amaximum of 5 carbon atoms; R, R and R are each independently alkylhaving a maximum of 20 carbon atoms and A is a pharmaceuticallyacceptable an- 1011.

In a preferred embodiment of this invention R R and R are eachindependently alkyl having a maximum of five carbon atoms.

In another preferred embodiment of this invention R is preferably alkylhaving at least 12 and a maximum of 18 carbon atoms.

In another preferred embodiment of this invention R and R are the sameand are alkyl having a maximum of 20 carbon atoms and R and R are thesame and are alkyl having a maximum of five carbon atoms.

With regard of the definition of R, the term alkyl" includes thealiphatic hydrocarbon groups which are derived from natural fats andoils. Such hydrocarbon groups contain primarily saturated linkages, butmay contain from one to four unsaturated linkages, and therefore aresometimes also referred to as alkylene groups. As used herein the termalkyl" therefore refers to both saturated alkyl and unsaturated alkylenegroups which contain from 12 to 22 carbon atoms. Animal fats and oilsand vegetable oils are sources of mixed alkyl groups where the alkylgroups contain predominantly from 16 to 18 carbon atoms. Whereunsaturated linkages are present, they can be converted to saturatedlinkages by hydrogenation. For example, alkyl groups derived from animalfats, such as tallow are composed predominantly of saturated C and Calkyl groups. More specifically, these are hexadecyl and octadecylaliphatic hydrocarbon groups, as derived respectively from palmitic andsteazric acids. Where un- I saturated C or C groups are present, such asthose derived from palmitoleic or linoleic acids, they can be completelyor partially converted to the saturated hexadecyl or octadecyl groups.In one embodiment of the present invention, long chain alkyl groups ofthe quaternary ammonium compound are provided by alkyl groups which areeither all saturated hexadecyl or octadecyl groups, or which areprovided by mixtures of alkyl groups wherein at least from to percent byweight of the alkyl groups are saturated C or C groups, that is,saturated hexadecyl or octadecyl groups.

Examples of pharmaceutically acceptable anions include, but are notlimited to, the halides (chloride, bromide and iodide), nitrates,nitrites, phosphates, sulfites, sulfonates, sulfates, acetates,citrates, tartrates, maleates, oxalates, cyclic acid salts, lactates,stearates and the like. The halides, especially the chlorides, are thepreferred anion.

Examples of alkyl groups useful in this invention include, but are notlimited to, methyl, ethyl, propyl, octyl, decyl, lauryl, myristyl,palmityl, stearyl, oleyl, linoleyl, arachadonyl and the like andmixtures of these groups.

The amines of this invention are: commercially available or are easilyprepared according to standard procedures which are within the skill ofthe ordinary chemist. For the amines having alkyl groups of C to C it ismore feasible to utilize mixtures of amines which are commerciallyavailable.

Quaternary ammonium compound tetracycline complexes are alsocommercially available or easily prepared utilizing standard procedures.The preparation of complexes is illustrated in US. Pat. No. 2,873,276.

The specific quaternary ammonium compounds which have been found usefulin the compositions of this invention include monotallowtrimethylammonium halides, especially monotallow trimethylammoniumchloride; tetramethylammonium iodide; diethyl dimethylammonium chloride;trimethylbenzyl ammonium chloride; trimethyl octadecyl ammoniumchloride; trimethyl cocodecylammonium chloride; trimethyldodecylammonium chloride; trimethyl hexadecylammonium chloride;trimethyl soya ammonium chloride; benzyl dimethylpentyl ammoniumchloride; dimethyl dioctadecylammonium acetate; dodecyldimethylbenzylammonium chloride; ethylbenzyldimethylammonium chloride;methyltrioctadecylammonium chloride; cetyl trimethylammonium bromide;tetraethylammonium bromide; trialkyloctadecyl ammonium stearate;trimethyl hexadecyl ammonium stearate; trimethyloctadecyl ammoniumphosphate, trimethyl chaulmoogrylammonium bromide; trimethylheptadecylammonium citrate; triethyl hydrocarpylammonium tartrate;stearyldimethylbenzylammonium chloride, and mixtures thereof.

The mechanism by which the effective compounds exert their activities isnot completely understood. The compounds are active only whenadministered to the female of the species. As it will be shown in theexperimental section, the administering of the active compoundsprevented conception in some species while in others there was evidenceof resorptions. The effective compoundn may thus be embryocidal,ovicidal and/or spermicidal.

The mode of administration is by any of the conventional means foradministering pharmaceutical preparations such as tablet, capsule,liquid and injection. In addition, and especially when administered toanimals, the active material may be incorporated in the animal feed orbait.

The compounds of this invention have been administered over the timeperiod from prior to mating to the period after mating but prior toimplantation of the egg or fertilized egg in the uterine wall. In mostinstances satisfactory results were obtained even though the compoundwas not administered until after mating.

Although the compounds have been found to exert a residual effect, it isrecommended that the compound be administered over a period of severaldays and preferably at the time of mating.

The time period which elapses between mating and the implantation and/orfertilization of the egg is known for the different female species andthus the time for beginning the administering of the composition iseasily calculated.

The tetracycline compound, when employed, and the quaternary ammoniumcompound are usually present in the complex in the approximate ratiorange (based on weight percent) of tetracycline to quaternary ammoniumcompound of 23/1 to /1.

The term mammal includes but is not limited to rodents, lagomorphs andinsectivores such as rats, mice, moles, ground hogs, nutria, bats,guinea pigs, gerbils,

rabbits and the like; carnivores, ungulates and primates such as cats,dogs, ferret, chimpanzees, and monkeys, as well as man.

In this specification and the appended claims, the term tetracycline" isbeing used to include tetracycline, oxytetracycline andchlortetracycline unless otherwise specified. The term complex isutilized to define the quaternary ammonium compound tetracyclinecomplex.

The compounds of the present invention can be prepared and administeredto mammals, i.e., humans and animals, in a wide variety of oral andparenteral dosage forms.

For preparing pharmaceutical compositions from the physiologicallyactive compounds of this invention, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations, include powders,tablets, dispersible granules, capsules, cachets and suppositories. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders or tablet-disintegrating agents; it can also be an encapsulatingmaterial. In powders the carrier is a finely divided solid which is inadmixture with the finely divided compound. In the tablets the compoundis mixed with carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain from 5 to 10 to 60% of the activeingredient. Suitable solid carriers include magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, alow melting wax and cocoa butter. The term preparation is intended toinclude the formulation of the compound with encapsulating material ascarrier providing a capsule in which the compound (with or without othercarriers) is surrounded by carrier, which is thus in association withit. Similarly, cachets are included. Tablets, powders, cachets andcapsules can be used for oral administration.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water-propylene glycol solutions forparenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solutions. Aqueous suspensionssuitable for oral use can be made by dispersing the finely-divided.compound in water with viscous material, natural or synthetic gums,resins, etc., for example, gum arabic, ion-exchange resins,methylcellulose, sodium carboxymethylcellulose and other well knownsuspending agents.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the compound. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, for example, packeted pow ders of vials or ampules.

The unit dosage form can be a capsule, cachet or tablet itself, or itcan be the appropriate number of any of these in packaged form. Thequantity of compound in a unit dose of preparation may be varied oradjusted from 5 mg. to 1000 mg. (generally within the range of 5 to 250mg.) according to the particular application intended and the potency ofthe active ingredient employed.

The claimed compositions having the stated physiological activity can beincorporated into pharmaceutical formulations includingsustained-release agents.

In use as an antifertility preparation, the preparations of the presentinvention are administered at the initial dosage of about 5 to 300 mg.per kilogram daily. The dosages, however, may be varied depending uponthe requirements of the subject.

It is understood that the pharmaceutical preparations described may beformulated in unit dosage form for veterinary use, and especially, foruse with cats and dogs.

In a related aspect, novel and useful compositions are provided in thisinvention which comprise at least one active ingredient compound withinthe scope of this invention in admixture with an animal feed, especiallyfor pets such as cats and dogs. Description of suitable feeds can befound in the book Feeds and Feeding by Frank B. Morrison, published bythe Morrison Publishing Company of Ithaca, N.Y., 1948, 21st Edition. Theselection of the particular feed is within the knowledge of the art andwill depend of course on the animal, the economics, natural materialsavailable, the surrounding circumstances and the nature of the effectdesired, as will be readily understood.

A particularly important composition according to this feature of theinvention is a concentrate, suitable for preparation and sale to afarmer or pet owner for addition to the animals feedstuffs inappropriate proportion. These concentrates ordinarily comprise about0.5% to about 30% by weight of the active ingredient compound togetherwith a finely divided solid, prefera bly flours, such as wheat, corn,soya bean, ground horse meat, fishmeal, and the like. Depending on theexcipient animal, the solid adjuvant can be ground cereal, fishmeal,charcoal, fullers earth, oyster shell, canned cat or dog food, and thelike.

The feed compositions, as well as the just-described concentrates, canadditionally contain other components of feed concentrates or animalfeeds, as will be readily understood. Other particularly importantadditives include proteins, carbohydrates, fats, vitamins, minerals,antibiotics, such as tetracycline compounds, etc.

Although the quaternary ammonium compounds of this invention may beincorporated into feed compositions, it is preferably that the activecompound be administered by way of a pharmaceutical composition in unitdosage form so as to regulate the amount of intake by the animal and tomake certain that an effective antifertility amount is consumed.

In accordance with another embodiment of this invention, the activequaternary ammonium salt is used in combination with a tetracyclinecompound such as oxytetracycline (Terramycin) or chlortetracycline(Aureomycin). The quaternary ammonium compound may be utilized as anentity separate from the tetracycline compound or the two entities maybe combined and utilized as a quaternary ammonium tetracycline complex.Tetracycline compounds of this invention are preferably tetracycline andits derivatives such as oxytetracycline (Terramycin) andchlortetracycline (Aureomycin).

It has been found that fertility can be controlled or reduced upon theadministration of 5 to 300 mgm/kg/day of the quaternary ammoniumcompound. The preferred rate of administration in general is from to 200mgm/kg/day. For given species the preferred range will of course vary,for example, for dogs and cats the presently preferred range is 10 tomgm/kg/day.

The amount of tetracycline associated with this range of quaternaryammonium compound, when the complexes are utilized, is easily calculatedfrom the above ratio range.

Administration of about 10 mgm/kg/day has been found to be extremelyeffective in the dog to prevent fertility.

The following examples illustrate the effectiveness of the compounds ofthis invention and the various time periods over which the administeringof the compounds were initiated.

EXAMPLE 1 This example illustrates the effectiveness of a quaternaryammonium-tetracycline complex.

A group of seven brood bitches known as breeders were divided into agroup of five and a control group of two dogs. Both groups of dogs werefed the same feed with the exception that a quaternaryammoniumtetracycline complex was added at a rate equivalent to 500 mgm.of terramycin per pound of feed. The ratio of terramycin to quaternaryammonium compound in this complex was approximately 5/1. The quaternaryammonium compound utilized was a commercial monotallow trimethylammoniumchloride or the formula [RN(CH CI wherein R had the approximatecomposition myristic C 1 4 3.0% pentadecylic G1 5 1.0% palmitic C- l 629.0% margaric C- l 7 1.5% stearic C-1 8 19.0% palmitoleic C-l6 3.0%oleic C-1 8 40.0% linoleic C- l 8 3.5%

. Based upon normal feeding habits of these dogs, it is calculated thateach dog consumed approximately l0-l2 mgm/kg/day of quaternary ammoniumcompound.

This group of five dogs was administered the complex for approximatelysix weeks prior to breeding.

The same stud dog was utilized in breeding both groups of dogs. The twocontrol dogs became pregnant and delivered normal litters of pups. Inthe group of five dogs which were administered the complex, no pregnancywas noted.

EXAMPLE 2 In a controlled experiment similar to Example I, the complexwas fed only to the stud dog and not to the females at the same rate asin Example 1. In all instances the females became pregnant.

EXAMPLE 3 TABLE I No. of No. of Intervening No. No.

Dogs Days Pregnancies Non-Pregnancies Comments 1 reduced litter 4 l7 2 ll aborted 8 l 3 5 Dogs bred more than 19 days prior to initiation ofadministration of the complex generally became pregnant and are notincluded in Table I. Likewise, dogs bred after initiation ofadministration of the complex generally did not became pregnant and thusthe results, which would only be cumulative, are not included in Tablel.

A review of Table I will show that for the control or reduction offertility in dogs, the administration of the active compound should beinitiated no later than 19 days after breeding and preferably withindays of breeding.

EXAMPLE 4 This example illustrates the effectiveness of quaternaryammonium compounds alone.

Three groups of rats, containing 5, 6 and 5 rats respectively, were feda feed to which was added a quaternary ammonium compound havingessentially the same composition as in Example 1. The rats receivedessentially the amount shown in Table II. The quaternary ammoniumcompound was administered to the rats for 14 days prior to breeding. Therats were sacrificed on the 16th day of gestation. The results obtainedare tabulated in Table II.

In Group 2 (30 mg/kg/day) normal developing feti were noted in eachcase. The number of feti in each animal varied as did the number ofresorption sites.

In Group 3 (3 mg/kg/day), four of the five rats (80%) developedapproximately the same number of normal feti. One rat had no feti orresorption sites.

Similar results were obtained at reduced rates when the compound wasadministered to dogs.

Similar results may be obtained utilizing either cetyltrimethylammoniumbromide, tetraethylammonium bromide, stearyldimethylbenzyl ammoniumchloride;

trimethyloctadecylammonium chloride; trimethylcocodecylammoniumchloride; trimethyldodecylammonium chloride; trimethylhexadecylammoniumchloride; trimethyl soya ammonium chloride; benzyldimethylpentylammonium chloride; dimethyldioctadecylammonium acetate; dodecyldimethylbenzyl ammonium chloride and trimethylhexadecylammonium stearate, as thequaternary ammonium compound. i

EXAMPLE 5 This example illustrates the apparent ineffectiveness oftetracycline alone.

As seen in Table II, the rats in Group 1 (300 mg/kg/day) showed nodevelopment of feti. The number of resorption sites in the uterusconfirms the fact that conception had taken place.

Three breeding females were fed 500 mgm per day, in two 250 mgm doses,of terramycin prior to breeding and for days post breeding. The resultsare tabulated in Table III. The number of days is the elapsed time 9 7from initiation of administering the active compound to TABLE v the daythe dog was bred.

TABLE III Animal No. of Live Offspring No. of Stillbirths ZEJ 5 2 FemaleNo. Days RESULTS QBH l 0 QEl 2 2 l 22 Pregnant QAF 0 0 2 24 Pregnant 8 83 l7 Pregnant QPX 0 0 l0 ZST 0 0 Q8] 0 0 These results are differentfrom the results shown in MMQ 0 0 Example 3 in which thequaternary-tetracycline complex was found to be effective and that theadmmlstra- A second group of five proven bitches were handled tron canbe initiated up to approximately 14-15 days 15 after breeding.

EXAMPLE 6 This example illustrates that, upon removal of the activecomponent, normal conception rates were obtained.

The feed of animals which contained the complex as in Example 3 wasreplaced with a feed free of the complex. The return of normalconception rates was tabulated in Table IV. The number of days is theelapsed time from withdrawal of the complex to date of breed The erraticnature of the early results of Table IV is due to the procedure in whichthe feed with complex was replaced with free" feed. Instead of removingall the feed with added complex and substituting free feed, free feedwas added to the medicated feed (feed with complex) and thus graduallydiluting the amount of complex in the feed.

EXAMPLE 7 This example illustrates the effectiveness of the quaternaryammonium compound in dogs when fed at two levels.

Ten proven bitches were fed the quaternary ammonium compound at 0.03% ofthe diet from the time of estrus until 65 days following mating. Thetable below presents the results of mating.

in an identical fashion except that the quaternary ammonium compound wasfed at 0.3% of the diet. None of the animals became pregnant.

From the above it can be seen that the quaternary ammonium compound at adietary level of 0.3% completely prevents pregnancy and that a level of0.03% dramatically reduces the rate of conception.

EXAMPLE 8 A feed for cats or dogs is prepared as follows:

Oat groats 350 lbs. Horsemeat, ground l000 lbs. Molasses I00 lbs.Soybean meal 450 lbs. Dried skim milk lbs. Ground limestone 20 lbs.Dicalcium phosphate 20 lbs. Salt plus trace mineral mix l0 lbs. Standardvitamin premix 1 lb.

2051 lbs.

EXAMPLE 9 A large number of unit capsules for oral administration areprepared by filling standard two-piece hard gelatin capsules weighingabout 50 milligrams each with 50 milligrams of powderedtrimethyloctadecyl ammonium chloride.

EXAMPLE 10 Example 9 is repeated except that soft gelatin capsules areuse, each also containing about 25 milligrams of stearic acid.

EXAMPLE 1 1 Example 9 is repeated except that the dosage unit is 50milligrams of active-ingredient, 2.5 milligrams of gelatin, 2.5milligrams of magnesium stearate and 100 milligrams of starch, mixed andformed into a tablet by a conventional tableting machine. Slow releasepills or tablets can also be used.

EXAMPLE l2 EXAMPLE 13 To prepare 1000 tablets, each containing 25 mg. ofmonotallow trimethylammonium chloride, the following ingredients areused:

monotallow trimethylammonium chloride 25.0 gm milk sugar 164.12 gmethylcellulose O 1 gm. corn starch l3.0 gm. sodium benzoate 0.02 gm.talc 4.7 gm. Acacia powder 2.5 gm. magnesium stearate 1.5 gm.

A tablet granulation is prepared from these ingredients by admixing saidactive compound with a starch paste comprising the corn starch, milksugar, sodium benzoate, ethyl cellulose and acacia powder in asufficient amount of water to provide a pasty consistency. The mixtureis worked until it granulates and then passed through a large meshscreen (e.g., no. 16). The granules are dried and then put through a no.20 screen and mixed with the previously sieved talc and magnesiumstearate. The resulting granulation is then pressed into tablets, eachcontaining the specified amount of active ingredient.

In the same manner, all the other compounds utilizable within thepurview of this invention may be tableted.

lt has been found that other quaternary ammonium compounds such ascetyltrimethylammonium bromide,

tetraethylammonium bromide, stearyldimethylbenzyl ammonium chloride,trimethyl octadecylammonium chloride, trimethyl cocodecylammoniumchloride, trimethyldodecylammonium chloride, trimethylhexadecylammoniumchloride, trimethylsoyaammonium chloride, benzyl dimethylpentyl ammoniumchloride, dimethyl dioctadecylammonium acetate, dodecyldimethylbenzylammonium chloride and trimethylhexadecyl ammonium stearate can also beformulated to provided an anti-fertility preparation of the same typeshown in Example 13, which acts as an effective antifertility agent whenadministered to cats and dogs in the manner of Example 4 or 7.

Although the above examples were limited to the effect on animals, thismethod is also effective when utilized by humans.

In addition, the administering of the active ingredient by adding to thefeed was for convenience only. As discussed previously, the otherstandard methods of administering pharmaceuticals is preferably utilizedinstead of adding the active component to the feed.

While the illustrative embodiments of the invention have been describedhereinbefore with particularity, it will be understood that variousother modifications will be apparent to and can readily be made by thoseskilled in the art without departing from the scope and spirit of theinvention. Accordingly, it is not intended that the scope of the claimsappended hereto be limited to the examples and the description set forthherein but rather the claims be construed as encompassing all thefeatures of patentable novelty which reside in the present inventionincluding all features which would be treated as equivalents thereof bythose skilled in the art to which the invention pertains.

What is claimed is:

l. A method for the control of fertility in a female mammal comprisingadministering to the female mammal at the time of mating or within aneffective period thereafter an anti-fertility effective amount of acompound selected from the group consisting of a. a quaternary ammoniumcompound of the formula wherein R is selected from the group consistingof alkyl having a maximum of 22 carbon atoms, phenyl, benzyl, R O- andHOR O, wherein R is alkyl having a maximum of 5 carbon atoms and R isalkylene having a maximum of5 carbon atoms; R R and R are eachindependently alkyl having a maximum of 20 carbon atoms; and A is apharmaceutically acceptable anion; and

b. mixtures of more than one such quaternary ammonium compound.

2. A method in accordance with claim 1 in which R R and R are eachindependently alkyl having a maximum of five carbon atoms.

3. A method in accordance with claim 2 in which R is alkyl having atleast 12 and a maximum of 18 carbon atoms.

4. A method in accordance with claim 1 in which the quaternary ammoniumcompound is complexed with a tetracycline.

5. A method in accordance with claim 4 wherein said quaternary ammoniumcompound complexed with the tetracycline is tallow trimethylammoniumchloride.

6. A method in accordance with claim 1 in which A is selected from thegroup consisting of halides, phosphates, sulfates, lactates andstearates.

7. A method in accordance with claim 1 in which said quaternary ammoniumcompound is a mixture of compounds having an R group containing from 12to 18 carbon atoms.

8. A method in accordance with claim 1 which com prises administering 5to 300 mg/kg/day of said quaternary ammonium compound in unit dosageform.

9. A method in accordance with claim 1 which comprises administering 5to 1000 mg. of tallow trimethylammonium chloride in unit dosage form.

10. A method in accordance with claim 1 in which said mammal is a dog.

weight daily in cat or dog food compositions.

13. A method according to claim 1, further comprising startingadministration of said compound after mating.

1. A METHOD FOR THE CONTROL OF FERTILITY IN A FEMALE MAMMAL COMPRISINGADMINISTERING TO THE FEMALE MAMMAL AT THE TIME OF MATING OR WITHIN ANEFFECTIVE PERIOD THEREAFTER AN ANTI-FERTILITY EFFECTIVE AMOUNT OF ACOMPOUND SELECTED FROM THE GROUP CONSISTING OF A. A QUATERNARY AMMONIUMCOMPOUND OF THE FORMULA
 2. A method in accordance with claim 1 in whichR2, R3 and R4 are each independently alkyl having a maximum of fivecarbon atoms.
 3. A method in accordance with claim 2 in which R'' isalkyl having at least 12 and a maximum of 18 carbon atoms.
 4. A methodin accordance with claim 1 in which the quaternary ammonium compound iscomplexed with a tetracycline.
 5. A method in accordance with claim 4wherein said quaternary ammonium compound complexed with thetetracycline is tallow trimethylammonium chloride.
 6. A method inaccordance with claim 1 in which A is selected from the group consistingof halides, phosphates, sulfates, lactates and stearates.
 7. A method inaccordance with claim 1 in which said quaternary ammonium compound is amixture of compounds having an R'' group containing from 12 to 18 carbonatoms.
 8. A method in accordance with claim 1 which comprisesadministering 5 to 300 mg/kg/day of said quaternary ammonium compound inunit dosage form.
 9. A method in accordance with claim 1 which comprisesadministering 5 to 1000 mg. of tallow trimethylammonium chloride in unitdosage form.
 10. A method in accordance with claim 1 in which saidmammal is a dog.
 11. A method in accordance with claim 1 in which saidmammal is a cat.
 12. A method in accordance with claim 1 which comprisesadministering said quaternary ammonium compound in the amount of about10 to 20 mgm/kg of body weight daily in cat or dog food compositions.13. A method according to claim 1, further comprising startingadministration of said compound after mating.